cervical cancer screening: new approaches - …cmetracker.net/eh/files/eventmaterials/19376/cervical...

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Levi S. Downs, Jr., MD Levi S. Downs, Jr., MD

Cervical Cancer Screening:Cervical Cancer Screening:New ApproachesNew Approaches

, ,, ,

Disclosures & images

During the previous 12 months, I have been a consultant for and received honoraria from Merck.

Images are attributed where appropriateNumerous images are utilized from :

ABS: Apgar, Brotzman, Spitzer. Colposcopy, 2nd Ed., 2008

ASCCP Modern Colposcopy, 2nd Ed., 2004

Unlabeled images are from the University of MichiganUnlabeled images are from the University of Michigan

All ASCCP Guidelines are from:Wright TC, Massad S, Dunton CJ, et al. J Lower Genital Tract Disease, 2007; 11: 201-222 and 2007; 11: 223-239

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ObjectivesObjectives

Early detection or prevention of cervical cancer

Prevent mismanagement of screening

Discuss current cervical screening guidelines:

ACS/ASCCP/ASCP Consensus American Cancer Society, American Society for Colposcopy and Cervical Pathology, American Society for Clinical Pathology. Obstet Gynecol 2012; 120: 1222-38

ACOGACOG P ti B ll ti #131 N b 2012ACOG Practice Bulletin #131, November 2012

U.S. Preventive Services Task ForceAnn Int Med 2012; 156: 880-91

Discuss ASCCP 2006 screening guidelinesRevisions due March 2013

Outline

The original Pap test

Better understanding of etiology and natural history

Evolution of cervical cancer screening

The newest guidelines for screening

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Median Age of Events Associated withMedian Age of Events Associated withCervical Infection by HR HPVCervical Infection by HR HPV

Menarche

1st intercourse1st intercourse

High-risk HPV Infection

ASC-US or LSIL and HPV positive

Pap normal, HPV (-), Type specific antibody (+)

CIN 3/ Carcinoma in situ, HPV (+)

10 15 20 25 30 35 40 45 50

Microinvasive cancer, HPV (+)

Invasive HPV(+)

Evolution of the Pap Test

PublicationsPublications

1917 ”A rhythmical ‘heat period’ in guinea pigs”in guinea pigs

1928 “New cancer diagnosis”

1933 “The sexual cycle in the human female as revealed by vaginal smears”

1941 Publication of “The diagnostic value of gvaginal smears in carcinoma of the uterus”

1949 Widespread introduction of the Pap test begins

Image from US Postal Service

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Cervical Cytology

Normal LSIL HSIL (CIN2)

HSIL (CIS) Invasive SCC

ASCUS

The Good News About Pap Tests:Cervical Cancer Mortality, 1950-2004

5-year mortality per5 year mortality, per 100,000 Caucasian females

American Cancer Society Statistical Report

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Annual contribution to squamous cervical cancer Annual contribution to squamous cervical cancer screening failure in USAscreening failure in USA

Why does screening fail?

% #

Never screened 50% 6280>5 yrs since screened 10% 1260False Negative Pap 30% 3770Errors in follow up 10% 1260

Total 100% 12,560

Sawaya Obstet Gynecol 1999

Retrospective Study of Cervical Cancers Diagnosed at Kaiser Northern California

Have causes of screening failures changed since 1999?

Pap results 3-36 months prior to diagnosis, N=833

Failure to screen

No Pap 464 56%

No visit: 19%

1-2 visits 18%

>3 visits 63%

Failure in detection: 1st Pap WNL 263 32%

Failure to follow-up: 1st Pap abnormal 106 13%

Leyden MA, Manos M, Kinney W et al JNCI 2005;97:67583

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System Failures Leading to Cervical Cancer Diagnosis

Health care providersdo not screen women

at visitsPatient does not get

Women do notcome in for

appropriate therapy

Patient gets cervical cancer

screeningColposcopy for

abnormal screennot done

Courtesy of Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD

Who are the rarely and never screened?

G % P t t

Proportion of Women Receiving Cervical Cancer Screening,National Health Interview Survey, United States, 2000

Group % Pap test

past 3 years

All women 82%

Insured

Yes

No

85%

62%

Country of birthCountry of birth

US born

Foreign born in U.S. <10 yrs

83%

61%

Swan et al, Cancer. 2003;97:1528-40

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Prevalence of pap tests during last 3 years by education level in the U.S.

https://www.cdc.gov/nchs/data/hus/hus07.pdf

2007. Health US 2007.CDC, National Center for Health Statistics.

How good is the Pap Test?How good is the Pap Test?

Meta-analyses: Biopsy proven CIN 2,3

Sens. Spec.Fahey 49% 62%Follen-Mitchell 67% 77%Nanda 51% 97%

Nanda K et al. Ann Intern Med 2000;132:810-9

Nanda 51% 97%

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Pap Test Evolution

AHCPR tAHCPR report on

Evaluation of Cervical Cytology

Meta-analysis of existing literature

Sensitivity

Conventional pap 51%

Liquid cytology 80%

AHCPR, Evaluation of Cervical Cytology, 1999

Conventional vs. Liquid Cytology: Another Meta-analysis

Arbyn et al, Obstet Gynecol 2008; 111: 167-77

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What has been done to improve screening?

Screening Interval

3 y 2 y 1 y

Decrease in incidence 51% 57% 70%Decrease in mortality 57% 61% 72%Decrease in simple hyst 44% 50% 64%Decrease in rad hyst 43% 50% 67%Decrease in rad hyst 43% 50% 67%Decrease in radiation 58% 65% 73%

AHCPR Evaluation of Cervical Cytology, 1999

Pap Test Evolution

Cost / life-year saved vs. no screening

Screening Interval Liquid ConventionalScreening Interval Liquid Conventional

One year $17,600 $13,271

Two years $8,882 $6,368

Three years $5,918 $4,079

ComparisonComparison

Mammogram cost / life-year saved is $50,000

AHCPR, Evaluation of Cervical Cytology, 1999

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Pap Test Evolution

1995 Automated re-screening system approved by FDA

1996 thin-layer cytology system approved by FDA

1997 Cell location system approved by FDA

1998 Computer assisted primary screening device approved by FDApp y

2001 The Bethesda System of nomenclature

2006 HPV Vaccine approved by FDA

“Finding lesions” is not the objective of screening?!

We can’t tell which lesions will progress

Emphasis should be placed on:

Persistent HPV infections

CIN 3 (no margin for error)

Persistent CIN 2 and CIN 2,3 in non-adolescent womenadolescent women

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What is the rationale for combined What is the rationale for combined screening with HPV test plus Pap?screening with HPV test plus Pap?

++

Premise for clinical use of HPV

Most HPV infections are transient—especially in young womenespecially in young women

Precancerous changes (HSIL) result from persistent HPV infections

Absence of HPV highly predictive of absence of CIN

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Cumulative incidence of HPVinfection from time of coitarche

Moscicki AB et al. J Adol Health 2005;37:S1-S9

The Probability of Clearing anHPV Infection

708090

10203040506070

Ho GYF et al, NEJM 1998; 328: 423-428

010

0 1 to 6 6 to 12 12 to 18

Months Since Positive Test

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HPV Prevalence and Cervical Cancer - Incidence by Age

25

30

Hi risk HPV

30

0

5

10

15

20

25 Hi risk HPVCancer

25

15

10

5

0

Sellors et al. CMAJ. 2000;163:503.

Ries et al. Surveillance, Epidemiology and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.

0

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

0

Prevalence of HPV by Age Manchester, U.K.

)P

erce

ntag

e H

PV

(+

Peto et al Br. J. Cancer (2004:91:942-53)

Age Group

14

4550

Prevalence of HPV types in females, ages 14-59, United States, 2003-2004 (NHANES)

51015202530354045

Pre

vale

nce

%

Low Risk

High Risk

05

14-19 20-24 25-29 30-39 40-49 50-59

Age, yrs

Dunne E, et al., JAMA, 2007

Sensitivity and specificity to diagnose CIN3 Sensitivity and specificity to diagnose CIN3

Cytology threshold LSIL or ASC-US X2

HR-HPV testing by HC2

Sens Spec Refer NPV

Pap 57.2% 89.9% 11.6% 98.4%Pap 57.2% 89.9% 11.6% 98.4%

HR-HPV 90.8% 72.6%72.6% 29.4% 99.6%

Kulasingam et.al. JAMA 2002;288:1749-57

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The Portland Kaiser Study 20,810 women followed for up to 122 months Over 45 mo incidence of CIN 3+ = 4 54% if HPV+

Combined HPV and Pap Testing Combined HPV and Pap Testing

Over 45 mo, incidence of CIN 3+ = 4.54% if HPV+ or Pap > ASC-US. If both neg, incidence = 0.16%

Efficacy of Pap (> ASC), HR-HPV, and Pap +HPV to predict CIN3+ within 45 mo.

Sensitivity PPV NPVPap + HPV 86.4% 4.54 99.8499.84ap 86 % 5 99 899 8Pap alone 49.2% 9.63 99.47HPV 75.4% 4.40 99.76

Sherman et.al. JNCI 2003;95:46-52

HPV Testing Requirements

Tests must be analytically and clinically validated

Proven acceptable reproducibility, clinical sensitivity, specificity, PPV and NPV for cervical cancer and CIN2/3

Based on FDA approval and/or publication in peer-reviewed scientific literature

Restrict testing to high risk HPV types Restrict testing to high risk HPV types

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FDA approved screening and triage

The first FDA approved test was:Hybrid Capture 2® (hc2), using a solution hybridization

th d T l d i l di HR

Low-risk

6, 11, 42, 43, 44

Because this is a cervical cancer triage test, HPV testing for ASC management and primary screening should be by high-risk panel only

method. Two panels were approved, including a HR panel with 13 types.

High-risk

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68


The second FDA approved test wasCervista® HPV HR, using an isothermal enzymatic DNACervista HPV HR, using an isothermal enzymatic DNA amplification process. The test detects 14 HR types.

High-risk

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68

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The FDA approved type-specific testing in 2009: pp yp p gCervista® HPV 16/18

Pitfalls of HPV DNA Testing

Positive HPV at any point in time may be from infection destined to resolve

HC2® reports “positive” at threshold of 1 pg/ml (5000 viral copies)

Report of “equivocal” or “indeterminate” if the levels approach thresholdNo clear next step – most labs recommend repeat

After cytology ~4-5% of specimens have i ffi i t li id f HPV t tiinsufficient liquid for HPV testing

HC2® and Cervista® have differing thresholds. The clinician should be aware of the potential impact upon clinical management.

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Negative HPV identifies a very low

Validation of Co-Testing and Screening Intervals

identifies a very low risk group, whether cytology is negative or not

Kaiser Study

N=331818 women age > 30 in prospective> 30 in prospective co-testing study

Katki HA, et al. Lancet Oncol 2011; 12: 663

HPV testing finds more women at high5-year risk of cancer or pre-cancer

Test 5 year Excess HPV Pap 5 year ExcessTest Result

5-year Risk

Excess Risk

HPV+ 7.6% 7.4%

RR 38HPV- 0.2%

Pap+ 4.7% 4.3%

RR 11 7Pap- 0 4%

HPV Test

Pap Test

5-year Risk

Excess Risk

HPV+ Pap+ 12% 6%

RR 2HPV+ Pap- 6%

HPV- Pap+ 0.9% 0.7%

RR 4 5HPV- Pap- 0 2%RR 11.7Pap 0.4% RR 4.5 HPV- Pap- 0.2%


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Proportion of CoProportion of Co--Test Results inTest Results in331,061 Kaiser Patients over 30331,061 Kaiser Patients over 30

2 4%

3.7% 1.4%

92.5%

2.4%

Discordant


Kaiser Northern California % Pap-/HPV

94 1%

813,000 co-tests

86 8%

89.3%90.4%

91.4%

92.3%

93.5%94.3%

94.1%

93.6%

93.3%

92.5%

Total = 90.9%

% P

ap-/

HP

V-

86.8%%

Castle PE, et al. Five-year experience of human papillomavirus DNA and Papanicolaou test co-testing. Obstet Gynecol 2009;113:595–600

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Percent of women Pap Normal / HPV positive

Kaiser/Northern California N = 813,000 co-tests

% P

ap-/

HP

V+

Total = 3.90%

6.76%

3.08%

2.89%

2.72%

2.56%

2.59%

3.81%5.01%

2.94%

2.87%

3.02%

Castle PE, et al. Obstet Gynecol 2009

What About HPV (+) and Cytology (-) ?

Rates of HPV persistence - 6 mos:Rates of HPV persistence 6 mos:

Clavel - France: 40%

Cuzick - England: 55%

Kinney-Kaiser @12 mo: 35%

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HPV (+) and Cytology (-)

Risk for CIN 2+ at 6 mos:

Cl l F 4 2%Clavel - France: 4.2%

Cuzick - England: 2.8%

Wright – South Africa: 7.8%

Clavel C et al Br J Cancer 2001;84:1616 1623Clavel C et al. Br J Cancer 2001;84:1616–1623Cuzick J et al. BMJ 2003;362:1871-76Wright TC et al. JAMA 2000;283:81-6

Proportion of CoProportion of Co--Test Results inTest Results in331,061 Kaiser Patients over 30331,061 Kaiser Patients over 30

2 4%

3.7% 1.4%

92.5%

2.4%


Baseline Pap %Neg 96.2

ASC-US 2.6LSIL 0.76AGUS/NOS 0.23ASC-H/HSIL/SCC 0.25

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Risk of Future CIN 3: Baseline HPV & Pap Test Concordance

Summary of Portland DataLorincz et al. Arch Pathol Lab Med 2003; 127: 959-968

BaselineStatus

N Woman yrs follow-

up

CIN 3N

Rate/100Woman Years

RR(95% CI)

Pap -HPV +

2561 10758 63 0.596 10.6410.64(7.3(7.3--15.5)15.5)

Pap -HPV -

17594 86210 48 0.056 1.0

Association of Initial Pap Abnormalities with Histology

Kaiser study

N=331

818 women age > 30 in prospective co-testing study

ASC-H/HSIL/SCC

LSILHPV+/Pap-

HPV+/ASC-US

AGUS/NOSLSIL

p

0 1 2 3 4 5

Years since enrolment


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Rate of cervical cancer following negative HPV test or normal Pap

For all women with normal Pap test:For all women with normal Pap test: 7.5 cervical cancers per 100,000 women / year

For all women HPV-negative: 3.8 cervical cancers per 100,000 women / year

For all women HPV-negative who also had a normal Pap test: 3 2 cervical cancers pernormal Pap test: 3.2 cervical cancers per 100,000 women / year


Cumulative Risk Of Invasive Disease Based on Initial Co-Test

Kaiser Study

N=331,818 women age > 30 in prospective co-testing study


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W th 21 Y

Updated Consensus Guidelines:When to begin screening

Women younger than 21 Years:

1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62: 147-72 and AJCP 2012; 137: 516 – 542.

2. Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: 880-913. ACOG Practice Bulletin #131, November 20124. NCCN Cervical Cancer Screening Guideline v. 2-2012.

www.NCCN.org

Rationale for Beginning Screening at Age 21Cervical Cancer Incidence by Age Group

USCS*, 1998-2002

Age Rate per 100,0000-19 0.120-29 4.530-39 13.940-49 16.550-64 15.465+ 14.6All ages 9.4

*United States Cancer Statistics includes data from CDC’sNational Program of Cancer Registries and NCI’s

Surveillance, Epidemiology and End Results Program.

Saraiya M et al. Obstet Gynecol 2007;109:360-70.

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Women older than 65 Years:

Updated Consensus Guidelines:When to cease screening

Screening should not be resumed for any reason, even if a woman reports having a new sexual partner.

Do not screen1. Saslow et al. ACS/ASCCP/ASCP. CA Cancer J Clin 2012; 62:

147-72 and AJCP 2012; 137: 516 – 542.2. Moyer VA, et al. USPSTF. Ann Int Med 2012; 156: 880-913. ACOG Practice Bulletin #131, November 20124. NCCN Cervical Cancer Screening Guideline v. 2-2012.

www.NCCN.org

Cessation of Screening

Adequate negative prior screening

is defined as:

3 consecutive negative cytology results

2 consecutive negative co-tests done within the 10 years before stopping screening with the most recent test within 5 years.y

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Evidence of adequate negative prior screening is not required

Updated Consensus Guidelines:Women with prior hysterectomy

Evidence of adequate negative prior screening is not required (all but USPST). Screening should not be resumed for any reason, including if a woman reports having a new sexual partner.



www.NCCN.org

Rationale for Stopping after Hyst

Vaginal cancer rate 7/million/year

663 vag cuff Paps needed to find one VAIN

2066 women followed after hyst for average 89 months:

3% had VAIN, 0 had cancer

Risk of Pap abnormality after hyst = 1%.

Comparable to risk of breast cancer in men Comparable to risk of breast cancer in men for which screening not recommended

Pearce KF et al. NEJM 1996;335:1559-62

Piscitelli JT et al. AmJOG 1995;173:424-30

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Updated Consensus Guidelines:Women with prior HPV Vaccination

Recommended screening practices should not change on the basis of HPV vaccination



www.NCCN.org

Not addressed

Both liquid-based and conventional smears are acceptable

Updated Consensus Guidelines:Screening Frequency

Both liquid based and conventional smears are acceptable. Co-testing should NOT be performed for women under age 30. Recommendations NOT intended for women with HIV,

immunocompromise, or in utero DES exposure



www.NCCN.org

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C t ti “ f d” d t l “ t bl ” b ll b t

Updated Consensus Guidelines:Screening Frequency

Co-testing “preferred” and cytology “acceptable” by all but USPSTF Recommendations NOT intended for women with HIV,

immunocompromise, or in utero DES exposure



www.NCCN.org

2006 ASCCP Guideline for Co-test Follow-up

Wright TC, et al. J Lower Genital Tract Disease, 2007; 11: 201-222 and 223-239

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Updated ASCCP Guideline for Co-test Follow-up

Wright TC, et al. J Lower Genital Tract Disease, 2007; 11: 201-222 and 223-239

UpdatesSaslow. CA Cancer J Clin 2012; 62: 147

RoutineCo-test in5 years

What is the recommended strategy to incorporate HPV-type Specific Testing?

There is no role for testing for low risk HPV ttypes

Testing for HPV 16/18 was approved in March 2009 by the FDA

Individuals with HPV 16 or 18 are at much higher risk of developing HSIL or cancer

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Percent of Squamous and AdenoCaof Cervix Due to HPV 16 or 18

90 86%

100

HPV 16 or 18

40

50

60

70

8070%

3030%

All other types

Munoz N et al. Int J Cancer 2004;111:278-85. [Evidence Level B]

Castellsague X et al. J Natl Cancer Inst 2006;98:303-15. [Evidence Level B]

0

Squamous cell carcinoma Adenocarcinoma

10

20 14%

Cumulative Incidence of CIN 3+ After Single HPV+Followed for 10 years Among Women > 30

HPV 16HPV 16

HPV 18

HR-HPV other than 16/18

HPV neg

Khan MJ et al. JNCI 2005;97:1072-9.

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Changes of HPV Type Prevalence by Lesion Severity

HPV Types in CIN 2, CIN 3 and Cervical CancerIceland, 1990-1994 and 1999-2003

Sigurdsson K et al. Int J Cancer 2007;2682-2687


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UpdatesSaslow. CA Cancer J Clin 2012; 62: 147

Co-test5 years

Colposcopy

Fundamental Principles

The goal of cervical cancer screening is the identification and treatment oftrue cervical cancer precursors

Persistent hi-risk HPV, CIN2 and CIN3 are accepted as cervical cancer precursors

Transient HPV infection, LSIL, and CIN1 are not considered cervical cancer precursorsprecursors

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The biggest gain in reducing cervical cancer incidence and mortality would be achieved by

Conclusion

incidence and mortality would be achieved by increasing screening rates among women who have not been screened or who have not been screened regularly. . .

ACS, 2002

Recommendation Caveats

Clinicians, patients, payers, IRBs, and the courts should never view recommendations as dictatesshould never view recommendations as dictates. Strong recommendations based on high-quality evidence will not apply to all patients.

Users of guidelines may reasonably conclude that following guidelines will be a mistake for some patients.

However, screening in excess of guidelines has been shown to cause potential harm to patients and to increase cost without sound justification

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What might a futurescreening strategy include?

New Biomarkers may enhance our ability to detect cancer precursors, e.g. DNA methylationdetect cancer precursors, e.g. DNA methylation of cell adhesion molecule 1, or expression of p16ink4A

When the HPV vaccine is fully deployed, the alteration of disease prevalence will greatly decrease the PPV of Pap testing. It is likely that primary screening will be based on HPV testingprimary screening will be based on HPV testing

2008 ASCCP Biannual Meeting

Questions?

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Citation SummaryABS: Apgar, Brotzman, Spitzer. Colposcopy, 2nd Ed., 2008

ACOG Practice Bulletin #131: Screening for Cervical Cancer, November 2012

ACS/ASCCP/ASCP Consensus Conference of American Cancer Society, American Society for Colposcopy andCervical Pathology American Society for Clinical Pathology Obstetrics & Gynecology 2012: 120: 1222-38Cervical Pathology, American Society for Clinical Pathology. Obstetrics & Gynecology 2012: 120: 1222 38.

ASCCP Modern Colposcopy, 2nd Ed., 2004

ASCCP Copyright 2004, 2009 American Society for Colposcopy and Cervical Pathology. All rights reserved.

Arbyn et al. Obstet Gynecol 2008; 111: 167-77

Castellsague X et al. J Natl Cancer Inst 2006; 98:303-15 [Evidence Level B]

Castle PE, et al. Five-year experience of human papillomavirus DNA and Papanicolaou test co-testing. ObstetGynecol 2009; 113:595-600

Clavel C et al. Br J Cancer 2001; 84:1616-1623

Connie Trimble, MD, Johns Hopkins University School of Medicine, Baltimore, MD

Cuzick J et al. BMJ 2003; 362: 1871-76

Dunne E, et al. JAMA 2007, 297(8): 813-819. doi:10.1001/jama.297.8.813

Ho GYF et al. NEJM 1998; 328: 423-428

Citation Summary (continued)

Katki HA, et al. Lancet Oncol 2012; 12:663 Khan MJ et al. JNCI 2005; 97:1072-9

Kulasingam et al. JAMA 2002; 288: 1749-57

Leyden MA, Manos M, Kinney W, et al. JNCI 2005; 97:67583Leyden MA, Manos M, Kinney W, et al. JNCI 2005; 97:67583

Moscicki AB et al. J Adol Health 2005; 37:S1-S9

Moyer VA, et al. USPSTF, Ann Int Med 2012; 156: 880-91

Munoz N et al. Int J Cancer 2004; 111:278-85. [Evidence Level B]

NCCN Cervical Cancer Screening Guideline v. 2-2012, www.NCCN.org

Nanda K et al. Ann Intern Med 2000; 132:810-9

National Center for Health Statistics, Health, US, 2007, Centers for Disease Control and Prevention, d / h /d t /h /h 07 dfwww.cdc.gov/nchs/data/hus/hus07.pdf

Pearce KF et al. NEJM 1996; 335:1559-62

Peto et al. Br. J. Cancer (2004:91:942-53)

Piscitelli JT et al. AmJOG 1995; 173:424-30

36

Citation Summary (continued)

Saraiya M et al. Obstet Gynecol 2007; 109:360-70

Saslow et al. ACS/ASCCP/ASCP Cancer J Clin 2012; 62: 147-72 and AJCP 2012; 137: 516-542

Sellors et al. CMAG. 2000; 163.503

Sherman et al. JNCI 2003; 95:46-52

Sigurdsson K et al. Int J Cancer 2007; 2682-2687

Swan et al, Cancer. 2003:1528-40

Wright TC, et al. JAMA 2000; 283:81-6

Wright TC, Massad S, Dunton CJ, et al. Journal of Lower Genital Tract Disease 2007, 11:201-22; 11:223-239.

cervical cancer screening: new approaches - …cmetracker.net/eh/files/eventmaterials/19376/cervical...

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